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Contents lists available at ScienceDirect

Journal of Intensive Medicine

journal homepage: www.elsevier.com/locate/jointm

Review

Antimicrobial stewardship and targeted therapies in the changing

landscape of maternal sepsis
Nishel M Shah 1,∗, Esmita Charani 2,3, Damien Ming 4, Fook-Choe Cheah 5, Mark R Johnson 1
1
Department of Metabolism, Digestion and Reproduction, Imperial College London, Chelsea and Westminster Hospital, London, UK
2
Health Protection Research Unit in Healthcare Associated Infection and Antimicrobial Resistance, Imperial College London, London, UK
3
Division of Infectious Diseases and HIV Medicine, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa
4
Department of Infectious Diseases, Imperial College London, Chelsea and Westminster Hospital, London, UK
5
Department of Paediatrics, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia

a r t i c l e i n f o a b s t r a c t

Managing Editor: Jingling Bao Pregnant and postnatal women are a high-risk population particularly prone to rapid progression to sepsis with
significant morbidity and mortality worldwide. Moreover, severe maternal infections can have a serious detrimen-
Keywords:
Sepsis tal impact on neonates with almost 1 million neonatal deaths annually attributed to maternal infection or sepsis.
Pregnancy In this review we discuss the susceptibility of pregnant women and their specific physiological and immunolog-
Immunology ical adaptations that contribute to their vulnerability to sepsis, the implications for the neonate, as well as the
Cardiovascular issues with antimicrobial stewardship and the challenges this poses when attempting to reach a balance between
Personalised medicine clinical care and urgent treatment. Finally, we review advancements in the development of pregnancy-specific
Antibiotic stewardship diagnostic and therapeutic approaches and how these can be used to optimize the care of pregnant women and
neonates.

Introduction
Sepsis has a significant contribution to both global morbidity
and mortality with approximately 30 million patients affected
worldwide each year and a resulting 6 million deaths.[ 1 , 2 ] Poor
outcomes from sepsis are a particular problem in certain vulner-
able populations which includes pregnant and postnatal women.
One in 10 deaths in pregnant and postnatal women worldwide
is attributed to sepsis[ 2 , 3 ] and one million neonatal deaths are
secondary to infection in pregnant women, including sepsis.[ 2 , 4 ]
Physiological adaptations during pregnancy are thought to con-
tribute to their vulnerability. In particular, changes in their car-
diorespiratory and immune systems, alongside physical, hor-
monal, and immunological changes during labor and postpar-
tum have been shown to have a significant impact.
ments in care. Age standardized infection rates have fallen from
800 per 100,000 pregnancies in 1990 to 550 per 100,000 preg-
nancies in 2019.[ 5 ] Despite this, in 2019 there were over 20
million cases of maternal sepsis and other maternal infections
worldwide. The World Health Organization (WHO) reported
global prevalence of maternal sepsis is 4.4%[ 5 , 6 ] . In the UK,
significant risk factors include ethnicity and deprivation. Black
and other ethnic minority groups are at an almost 2-fold in-
creased risk.[ 7 , 8 ] Furthermore, when compared to age-matched
non-pregnant controls, sepsis-related case fatality is higher dur-
ing pregnancy, childbirth, and postpartum.[ 9 ] The reasons for
the higher rates of sepsis-related maternal morbidity and mor-
tality are not fully understood.
Evidence for poor Outcomes from sepsis in pregnancy

Are Pregnant Women at Greater Risk of Sepsis? Data from current and previous coronavirus pandemics as
well as influenza and Ebola demonstrate the increased risk of
Morbidity and mortality from sepsis in pregnancy worldwide severe infection during pregnancy and poorer outcomes. [ 10–14 ]
have gradually been falling over the decades due to improve- For example, in pregnancy the risk of viral pneumonia and

∗
Corresponding author: Nishel M Shah, Department of Metabolism, Digestion and Reproduction, Imperial College London, Chelsea and Westminster Hospital,
London SW10 9NH, UK.
E-mail address: nishel.shah@imperial.ac.uk (N.M. Shah).

https://doi.org/10.1016/j.jointm.2023.07.006
Received 6 April 2023; Received in revised form 4 July 2023; Accepted 30 July 2023. Managing Editor: Jingling Bao
Available online xxx
Copyright © 2023 The Author(s). Published by Elsevier B.V. on behalf of Chinese Medical Association. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Please cite this article as: N.M. Shah, E. Charani, D. Ming et al., Antimicrobial stewardship and targeted therapies in the changing landscape of
maternal sepsis, Journal of Intensive Medicine, https://doi.org/10.1016/j.jointm.2023.07.006
JID: JOINTM
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N.M. Shah, E. Charani, D. Ming et al.
subsequent respiratory complications is far greater when com-
pared to the general population.[ 15 ] During the coronavirus 2
(SARS-CoV-2) pandemic, pregnant patients with severe acute
respiratory syndrome were more likely to require intensive care
and mechanical ventilation, and their mortality rate was higher
when compared to non-pregnant women.[ 12 ] Other pathology
such as renal failure and disseminated intravascular coagulopa-
thy (DIC) have also been shown to be more frequent in preg-
nancy. These vascular changes appear to extend to the placenta
where findings consistent with abnormal blood flow and ex-
tensive thrombotic vasculopathy have been observed in women
delivered during acute infection.[ 14 ] During antenatal bacterial
sepsis, obstetric complications associated with abnormal utero-
placental blood flow such as fetal growth restriction, placen-
tal abruption, and preterm birth are more common.[ 16 ] This
has also been shown in lipopolysaccharide (LPS) treated rats,
simulating sepsis during pregnancy, where coagulopathy, struc-
tural abnormalities in the uteroplacental vasculature, and de-
creased placental blood flow lead to fetal hypoxia and preg-
nancy loss.[ 17 ]
Period of greatest risk and associative factors in pregnancy
The stage of pregnancy and postpartum is also important.
Almost 34% of all maternal infections occur in the antenatal pe-
riod. Moreover, of those infections that are complicated or se-
vere, 17% and 28% respectively occur in the antenatal period.
In comparison, 60% of all maternal infections occur during the
intrapartum and postnatal periods, and they account for 60% of
both complicated and severe infections.[ 18 ] Prospective studies
conducted in the UK suggest that labor and the puerperium carry
a much higher risk, approaching a 2–3-fold increase in risk when
compared to the antenatal period.[ 19 ] It is possible that peripar-
tum and postnatal invasive interventions such as Caesarean sec-
tion and instrumental delivery, as well as intrauterine or vaginal
tamponade for massive obstetric haemorrhage, increase the risk
of developing infection.[ 7 , 20 , 21 ] These interventions have been
the target of efforts to reduceis infection rates by changes in ob-
stetric care and optimized use of antibiotic prophylaxis.[ 22 , 23 ]
The promotion of aseptic techniques and antibiotics are of par-
ticular need in Low and Low Middle Income Countries (LMIC),
where rates of maternal infections and severe maternal infec-
tions are 40% and 20% greater respectively than upper-middle
income countries, and fatality following puerperal infection is
as high as 50%.[ 6 , 18 ]
As discussed above, severe respiratory complications are
more common in pregnancy during severe infection, and so are
other downstream effects such as DIC, renal failure, and hy-
potension, which contribute to the rapid progression to sep-
tic shock. In a mouse model of LPS induced sepsis response,
pregnancy was found to be associated with a profound hy-
potensive response and increased mortality when compared
to non-pregnant mice.[ 24 ] In a second series of experiments,
using a polymicrobial sepsis model caused by caecal ligation
and puncture the same research group found that pregnancy
was again associated with a marked hypotensive response and
much greater mortality.[ 25 ] Interestingly, the use of broad-
spectrum antibiotics and a vascular smooth muscle specific
inhibitor of nitric oxide synthesis was associated with better
outcomes.[ 26 ] This suggests that identification and treatment
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are important tools to improve poor outcomes. In humans, cer-
tain pathogens predominate. In maternal sepsis, Escherichia coli
(E. coli) and group B Streptococcus (GBS) are the most com-
mon bacterial pathogens, although other causative organisms
include other Gram-negative organisms such as Klebsiellas, My-
coplasma, and other coliforms, but also Gram-positive organisms
such as Clostridium sordellii.[ 27 ] However, the most severe out-
comes are associated with E. coli and group A Streptococcus
(GAS).[ 19 ] Progression to septic shock is particularly a problem
with GAS infection.[ 28 ] Furthermore, in pregnancy, the risk of
group A and group B streptococcal bacteremia when compared
to non-pregnant women is 20–100-fold higher.[ 29 , 30 ]
Why are Pregnant Women at Greater Risk of Sepsis?
Physiological changes in pregnancy such as immunological,
cardiovascular and respiratory adaptations (Figure 1) may con-
tribute to an increased risk of developing severe complications
during sepsis.
Immunological
Peripheral blood adaptations
The earliest hypothesis proposed in the 1950′s described the
immune adaptations of pregnancy as a series of changes de-
signed to prevent rejection of the semi-allogenic fetus result-
ing in maternal immune tolerance.[ 31–33 ] Subsequently, the clas-
sic model of immune tolerance included a shift in T-helper
subsets (Th1 to Th2) that favored an anti-inflammatory pro-
file but also increased susceptibility to infections in pregnancy.
Our current understanding is that the immune environment
transitions with advancing gestation from a pro- to anti- and
back to a pro-inflammatory state.[ 34–36 ] The innate and adaptive
arms of the immune response are thus differentially activated to
modulate these changes as well as compensate for each other.
Immune modulation is thought to be influenced and main-
tained by endogenous factors that include feto-placental de-
rived antigens and pregnancy hormones such as oestrogen and
progesterone.[ 37–39 ] Fetal antigens elicit tolerogenic humoral
and cellular responses in pregnant women through the gener-
ation of antigen specific CD4 and CD8 T cells, MHC-specific B
cells (in murine models), and fetal-specific CD4 T-regulatory
cells (Tregs). [ 40–42 ] The placenta is the likely source of fetal
antigen exposure that is shed through microvesicles and exo-
somes, cellular debris and due to microchimerism.[ 43–47 ] Pro-
gesterone is a key hormonal modulator of immune responses
in pregnancy that acts to suppress inflammatory and cytotoxic
functions.[ 36 , 48–50 ]
Altogether, these changes described above result in a dy-
namic immune system in pregnancy that varies throughout ges-
tation. In early pregnancy, we see T cells resembling a Th1 phe-
notype and Tregs that favor an effector subset.[ 51 , 52 ] As preg-
nancy progresses into the second trimester the immune envi-
ronment becomes more immune tolerant. Thus, effector mem-
ory T cells predominate with upregulation of inhibitory mark-
ers, increased progesterone sensitivity of natural killer (NK)
cells, altered dendritic cell (DC) subsets and indoleamine 2,3-
dioxygenase activity, and a shift in Treg phenotype from ef-
fector to naive.[ 35 , 36 , 52 ] Finally, in the third trimester there
is a move to favor immune activation with pro-inflammatory
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Figure 1. Physiological adaptations in pregnancy. The respiratory, cardiovascular, and renal changes that occur in pregnancy. Immune changes are subdivided into
systemic and local changes that enable fetal tolerance. These adaptations contribute to the increased risk of maternal sepsis.
ERV: Expiratory reserve volume; FRC: Functional residual capacity; GFR: Glomerular filtration rate; ILC: Innate lymphoid cells; NK: Natural killer.
antigen-specific cellular responses that are further enhanced
during labor.[ 36 , 38 ]
Immune adaptations at the maternal-fetal interface
Modulation of immune responses is also evident locally at
the maternal-fetal interface and is seen in both the innate and
adaptive arms that include NK cells, innate lymphoid cells
(ILCs), and T cells. Importantly, this interface tolerates the semi-
allogeneic fetus but can retain an ability to protect against in-
vading pathogens. In fact, 30–40% of decidual cells are leuko-
cytes and this forms a specialized decidual immune system in
pregnancy.[ 53 ] Uterine NK cells (uNK) from a large portion of
innate leukocytes in the endometrium and decidua and they
function to facilitate placentation during pregnancy. Crucially,
the uNK phenotype changes during early pregnancy from proan-
giogenic to cytokine producing, thus allowing for extravillous
trophoblast invasion.[ 54 , 55 ] Their cytotoxicity is largely limited
due to their ability to interact with human leucocyte antigens
(HLA) class I molecules expressed by trophoblast (HLA-C, HLA-
E, HLA-G). With labour onset, the decidual NK phenotype shifts
resulting in a reduction in proportions of cytokine producing
CD56hi NK (our unpublished observations). This is consistent
with single cell RNA-seq data from the placenta, which has
demonstrated an upregulation of NK cell signatures.[ 56 ] This
suggests that the composition of the uNK compartment is dy-
namic. Strunz et al.[ 57 ] identified a subset of highly prolifera-
tive uNK cells that regenerate under the influence of sex hor-
mones and genetic triggers, for example during menstruation
and pregnancy. Whilst these cells differentiate locally their ori-
gin appears to be from the peripheral circulation and they are
transiently tissue-resident.
Another group of tissue resident immune cells important for
pregnancy is innate lymphoid cells (ILCs), which have been
identified in the uterus and decidua. These have immune modu-
latory functions and provide protection against pathogens. They
are subdivided into group 1 which produces mostly Interferon
(IFN)-𝛾, group 2 which produces Th2 cytokines, and group 3
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which produces Interleukin (IL)-22 and IL-17. In the decidua
during pregnancy, ILC2 is thought to be the most abundant sub-
set present.[ 58 ] However, ILC1 and ILC3 may have key roles dur-
ing certain pregnancy pathology, including preterm labor (PTL),
as well as during physiological labor. Furthermore, during preg-
nancy, the composition of these cells in the decidua basalis and
parietalis is different and may represent a varied immune re-
sponse. For example, Mendes et al.[ 59 ] demonstrated an increase
in ILC2 and ILC3 populations in the decidua basalis in PTL, and
similarly, Xu et al.[ 58 ] saw increases in both basalis and pari-
etalis.
Tissue resident macrophages are situated close to decidual
natural killer (dNK) cells. They function to clear debris, present
feto-placental antigens and secrete cytokines and chemokines to
modulate dNK and T cell responses.[ 60 , 61 ] Both CD8 and CD4 T
cells can directly (via HLA-C) or indirectly (via antigen process-
ing cells or APCs) recognize feto-placental antigens. However,
antigen specificity provides a means to regulate T cell immune
responses to prevent fetal rejection. For example, CD8 T cells ex-
pressing inhibitory markers (T cell immunoglobulin and mucin
domain-containing protein 3 or Tim-3, Programmed cell death 1
or PD-1) that interact with their ligands (Programmed cell death
ligand 1 or PD-L1) on trophoblast are enriched in the decidua
in an HLA-C dependent manner.[ 62 ] Moreover, the cytotoxic po-
tential of the effector memory CD8 T cell subset is impaired.[ 63 ]
Further regulation is provided by decidual fetal-specific Tregs
that clonally expand during pregnancy.[ 42 ] In murine models,
these have been shown to have fetal-specific and highly sup-
pressive capabilities.[ 64 ] In addition, class-switched memory B
cells and IL-10-producing B cells have been found co-localized
in clusters with Tregs in pregnancy further enhancing the regu-
lation of local immune responses.[ 65 ]
Immune contribution to sepsis
Antenatal responses to infections and vaccines are an op-
portunity to understand how pregnancy may affect adaptive
immunity. Forbes et al.[ 66 ] showed impaired in vitro antiviral
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N.M. Shah, E. Charani, D. Ming et al.
IFN responses in the second and third trimesters following rhi-
novirus infection. In contrast, analysis of ex vivo responses fol-
lowing influenza vaccine and SARS-CoV-2 infection fare differ-
ently, with maintenance of both humoral and antigen-specific
responses.[ 67–69 ] This suggests that cellular responses are un-
affected by pregnancy immune modulation. However, pheno-
typic data from the same research studies suggest a reduction
in the pro-inflammatory cellular compartments and low-level
immune regulation.[ 67 , 68 ] With peripartum risks much greater
than during the antenatal period, labor, which is itself a process
of inflammation, provides an opportunity to understand how
inflammatory responses are regulated. Tissue necrosis because
of inflammation can release microparticles to interact with in-
nate immune receptors such as toll-like receptors (TLRs) to drive
inflammatory signals during labor.[ 70 , 71 ] Interestingly, TLR in-
hibitors can repress this output.[ 70 ] As discussed earlier, in preg-
nancy many regulatory immune cells are upregulated, including
Tregs, and these have a suppressive effect on certain immune
responses.[ 39 ] Tregs can modify their targets from Th1 to Th2
effector T cells alongside a change in their suppressive activ-
ity to either suppress or propagate inflammation. Whilst during
sepsis Tregs are thought to have a protective effect by suppress-
ing exaggerated inflammatory immune responses, their abun-
dance in pregnancy may not necessarily be helpful in certain
circumstances.[ 72–74 ] For example, during labor Treg function
is thought to be altered to enable a proinflammatory cytokine
response.[ 38 , 39 ] This suggests that immune regulation during the
peripartum period may, in fact, result in an augmented inflam-
matory response to sepsis. In addition to this, leucocyte traffick-
ing may also be altered in pregnancy meaning that important
immune cells are less able to clear pathogens at sites of infec-
tion. This is shown in murine work using knockout mice which
demonstrates that the loss of a monocyte chemoattractant re-
ceptor leads to reduced cell trafficking, significantly worse bac-
teremia, and survival.[ 25 ] Furthermore, the migratory potential
of important immune cells required during an infection such
as neutrophils varies with gestation and during different labor
phenotypes.[ 75 , 76 ] These areas of immune modulation are all
possible avenues of future research and treatment options.
Cardiovascular
Circulatory adaptations
Cardiac output increases gradually in pregnancy, reach-
ing up to 45% greater than early pregnancy by 24 weeks of
gestation.[ 77 , 78 ] This occurs due to changes in stroke volume
and heart rate and is associated with both left and right ven-
tricular hypertrophy. Alongside these changes, peripheral vas-
cular resistance falls in the second trimester and reaches a nadir
of 40%.[ 77 ] Blood pressure (BP) dynamics show similar changes
with a fall in both systolic and diastolic, and therefore mean
arterial BP in early pregnancy that falls further in the sec-
ond trimester before increasing in the third.[ 79 ] Some of these
changes are hormone driven. For example, higher concentra-
tions of progesterone and relaxin are associated with lower sys-
tolic BPs.[ 80 ]
Renal adaptations
Plasma volume and red cell mass increase with advancing
gestation. This is due to activation of the renin-angiotensin-
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aldosterone (RAA) system that helps to maintain BP. Much
of this is due to the fact that progesterone, which also rises
in pregnancy, has potent mineralocorticoid effects, and acts
as an aldosterone antagonist to inhibit aldosterone binding.
This leads to compensatory RAA activation and a rise in
serum aldosterone.[ 81 , 82 ] Furthermore, relaxin stimulates vaso-
pressin secretion causing further water retention. The increase
in plasma volume and cardiac output alongside renal vasodilata-
tion, lead to an increase in renal plasma flow and glomerular
filtration rate.
Kidney size also increases in pregnancy with physiological
dilatation of the collecting ducts that causes hydronephrosis in
most pregnant women. This hydronephrosis increases with ges-
tation and is greater on the right kidney due to the compressive
effect of the gravid uterus.[ 83 ]
Cardiovascular contribution to sepsis
Increased levels of prostaglandins and nitric oxide (NO),
which are upregulated by oestrogen, encourage smooth muscle
relaxation and vasodilatation. During sepsis, further upregula-
tion of NO leads to the development of septic shock.[ 84 ] In addi-
tion, during sepsis, inflammatory cytokines such as tumor necro-
sis factor (TNF)-𝛼 and IL-1𝛽 lead to myocardial depression.[ 85 , 86 ]
Furthermore, measurable levels of serum Troponin T and I,
and B-type natriuretic peptide (BNP) have been shown to be
increased with sepsis-associated myocardial depression.[ 87–89 ]
These are useful markers for myocardial function and prognosis
in sepsis. Considering that cardiac output is increased in preg-
nancy, a loss of myocardial function has a significant effect on
the circulatory system. Downstream complications of severe sys-
temic infections include acute kidney injury, which is associated
with significant morbidity and mortality.
Renal contribution to sepsis
Physiological hydronephrosis and the mechanical compres-
sion of the ureters by the gravid uterus cause urinary stasis. This
alone can increase the risk of bacteriuria and ascending urinary
tract infection in pregnancy by up to 40%.[ 90 ] Furthermore, re-
nal tubular epithelial cells can interact with inflammatory me-
diators generated during infections through pattern recognition
receptors (PRRs) such as TLRs.[ 91 ] This interplay can exacerbate
local tissue injury. During sepsis, tissue inflammation, microvas-
cular injury, hypoperfusion, and organ dysfunction ensue as a
cascade of events. Local inflammatory responses form an im-
portant part of the host’s defense against invading organisms.
This is mediated by the interaction between pathogen associated
molecular patterns (PAMPs) and danger associated molecular
patterns (DAMPs) released into the vasculature during the initial
innate immune response and TLRs found on immune cells.[ 92 ]
Renal vascular and tubular epithelial cells also express TLRs
and their activation leads to the production of reactive oxygen
species (ROS) and cytokine signaling to attract leucocyte infil-
trates. The consequent endothelial injury and tubular inflamma-
tion lead to microthrombi formation, interstitial oedema, and
further tissue injury.[ 93 ]
Respiratory
Respiratory adaptations
In pregnancy, there is an increase in oxygen consumption and
progressive distension of the uterus that affects both metabolic
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N.M. Shah, E. Charani, D. Ming et al.
demands and lung volume. To try to maintain the total lung ca-
pacity, the volume of air remaining in the lungs post-exhalation
measured as functional residual capacity (FRC) and expiratory
reserve volume (ERV) is reduced.[ 94 ] In addition, there is an in-
crease in the tidal volume, which results in greater minute ven-
tilation without increasing the respiratory rate.
Respiratory contribution to sepsis
The adaptations in pregnancy including the physiological hy-
perventilation result in a state of respiratory alkalosis. This is
in part due to progesterone, which increases the sensitivity of
the respiratory center to carbon dioxide.[ 95 , 96 ] To maintain acid-
base balance, this alkalosis is managed by an increase in renal
bicarbonate excretion.[ 94 ] Consequently, the pregnant woman’s
capacity to counter sepsis-related metabolic acidosis may be sig-
nificantly impaired. This is an important consideration for all
forms of sepsis in pregnancy.
During respiratory tract infections, local responses to inflam-
mation are important in the context of pregnancy. As discussed,
pregnant women have been disproportionately affected during
respiratory pandemics. It is possible that these outcomes are
likely to be made worse by the compressive effect of the gravid
uterus on the maternal lungs and the greater chance of basal at-
electasis during late pregnancy.[ 94 ] One of the drivers of clinical
severity in these patients is thought to be a heightened cytokine
response, which has been observed previously during the H1N1
influenza pandemic.[ 97 ] A similar mechanism is thought to be at
play during the COVID-19 pandemic. However, acute changes
in the lungs may also be affected by pregnancy-specific inflam-
matory leucocyte sequestering in lung tissue during a cytokine
storm, as shown in murine pregnancy sepsis models, eventually
causing severe tissue damage.[ 24 ]
What are the Neonatal Consequences of Maternal Sepsis?
For the neonate, maternal transmission of bacteria such
as GBS or transmission of infections such as chorioamnionitis
during the intrapartum period significantly increases the risk
of early onset neonatal sepsis (EOS).[ 98 ] In addition, neona-
tal immune function during PTL with chorioamnionitis is as-
sociated with greater inflammatory cytokines and leucocyte
activation.[ 99 ]
Early neonatal sepsis
Unsurprisingly, rather like maternal sepsis, the most com-
mon pathogens involved are GBS and E. coli, accounting for ap-
proximately 70% of cases of EOS.[ 100 , 101 ] Whilst the overall in-
cidence of EOS is 1–2 per 100 live births, mortality from EOS
approaches 3% amongst term newborns and 16% in high risk,
low birth weight (LBW) neonates.[ 98 ] Interestingly, as causative
agents identified in neonates, GBS appears to affect more term
neonates and E. coli predominantly preterm infants, with the lat-
ter slowly on the rise. However, other organisms include Strep-
tococcus species and Haemophilus influenzae.[ 101 ]
Significant morbidity from EOS disproportionately af-
fects preterm neonates, who in the acute phases often
developing respiratory distress requiring invasive ventilation,
and hyper/hypo-glycemia. In the long term, these neonates are
at risk of bronchopulmonary dysplasia (BPD), a poor neurode-
velopmental outcome, and cerebral palsy. Term neonates with
5
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Journal of Intensive Medicine xxx (xxxx) xxx
EOS, commonly by GBS, can have significant neurological se-
quelae including seizures, blindness, hearing loss, and speech
and language delays.[ 100 ]
Rates of EOS are higher in some LMICs where the reported
incidence of peripartum infection is 4% but symptom reporting
suggests a much more plausible 16%. Early neonatal mortality
due to puerperal sepsis carries a relative risk of 2-fold when
compared to neonatal deaths in the absence of maternal infec-
tion. The authors of the study using demographic health survey
data from five LMICs suggest that inadequate reporting of ma-
ternal sepsis is a significant challenge in the study countries, and
improved recognition and treatment of maternal infections may
reduce neonatal complications.[ 102 ]
Maternal to fetal transmission
During sepsis in pregnancy, vertical transmission to the
neonate of the causative organism as well as transmission of
maternal colonising organisms (such as GBS) is more likely in
the presence of other infectious morbidities. These include risk
factors such as prolonged rupture of membranes or intrapartum
fever that increase the impact and risk of EOS[ 98 ] . Generally, in
both these circumstances, the risk of EOS increases 3–4-fold, and
50–67% of these involve preterm or LBW neonates.[ 103 ] The pro-
gression of ascending lower genital infections will be further ex-
acerbated by inflammation at the maternal-fetal interface. This
causes local immune defenses to be more permeable to invading
organisms, and can also lead to infections overwhelming host
responses.[ 104 , 105 ]
Other potential sources for vertical transmission of infec-
tions are maternal urinary tract infections and respiratory
infections. Urosepsis in pregnancy is a potential source of
Gram-negative bacteremia and is associated with poor neonatal
outcomes includingsepticemiaepticaemia, preterm births, and
stillbirths.[ 106 ] Although the mechanism for the relationship is
not clear, the prevalence of neonatal urinary tract infections
in those born to mothers with a corresponding urinary infec-
tion is relatively increased.[ 107 , 108 ] Data from LMIC suggest that
neonates born to mothers who experienced urinary tract infec-
tions during pregnancy are 3.55 times more likely to develop
neonatal sepsis when compared to those born to mothers with-
out a urinary tract infection.[ 109 ] It is plausible that untreated
ascending urinary infections in pregnancy that lead to sepsis
may result in fetoplacental transmission through hematogenous
spread to infect the neonate.
Respiratory tract infections are another common source of
maternal sepsis. Bacterial pneumonia is associated with worse
neonatal outcomes that include preterm birth, low birth weight,
and pre-eclampsia.[ 15 , 110 ] This is after accounting for comorbidi-
ties such as obesity and diabetes. However, the mechanisms for
these differences are unknown. While EOS is rare, it remains
possible in the presence of maternal bacteremia. Likewise, dur-
ing COVID-19 infection, pregnant women are more likely to de-
velop severe illness with an increased risk of preterm birth and
small for gestational age babies.[ 111–114 ] These neonatal com-
plications are more prevalent in moderate to severe COVID-
19.[ 115 ] However, early neonatal COVID-19 infection is rare and
neonatal symptoms are generally mild.[ 116 ] The source of ver-
tical transmission remains uncertain and appears to be unlike
other viruses such as Zika where trophoblast infection serves
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N.M. Shah, E. Charani, D. Ming et al.
as a route of transmission.[ 117 ] Viral entry is possible through
the angiotensin converting enzyme-2 (ACE-2) receptor isolated
on placental tissue and following placental barrier damage sec-
ondary to local inflammation and tissue injury.[ 118–120 ] Indeed,
the SARS-CoV-2 virus has been detected in syncytiotrophoblast
and other placental tissues, and the presence of the virus has
been shown to induce a robust immune response.[ 120–122 ] In
placentas with a high viral load, the maternal space, and fe-
tal chorionic villi are occupied by extensive inflammatory infil-
trates that comprise macrophages and T cells, and CD56+ NK
cells within the decidua.[ 121 ] A similar T cell infiltrate is seen in
the fetal chorionic plate. Moreover, ACE-2 receptors which are
detectable in fetal kidney, rectum, and ileum, are barely seen in
fetal lungs, brain, or heart towards term pregnancy.[ 123 ] In fact,
surveillance data suggests that postnatal transmission (via res-
piratory spread, close contact) accounts for most cases of early
neonatal infections.
Ultimately the risk of vertical transmission will depend on
the maternal system infected, the quality of maternal immune
response, the receptiveness of the fetal compartment, and the
evasive nature of the organism in question.
Management of early neonatal sepsis
National Institute for Health and Care Excellence (NICE)
guidelines for the management and treatment of neonatal infec-
tion (NG195), which includes EOS, comprises empirical treat-
ment based on maternal risk factors and neonatal clinical re-
view at birth.[ 124 ] Thereafter, the duration of treatment is based
on clinical improvement, neonatal blood cultures results, which
have notoriously poor sensitivity, and changes in non-specific
inflammatory markers, namely C-reactive protein (CRP).[ 125 , 126 ]
However, in the era of better antibiotic stewardship, the useful-
ness of empirical treatment based on maternal risk factors in
‘well’ infants is debatable, and tools to determine a baby’s risk
of developing EOS may be helpful in some cases.[ 125 ] Having
said this, it is important to note that neonatal antibiotic stew-
ardship is mired by challenges, including difficulties in devel-
oping unit antibiograms, and a lack of robust antibiotic trials
in neonatal populations.[ 127 ] There are also challenges with us-
ing diagnostic tools in neonatal populations. Research compar-
ing using the Kaiser Permanente sepsis risk calculator (SRC) to
standard NICE guidelines across 8 maternity units in Wales by
Goel et al.,[ 125 , 128 ] suggests that the use of the tool would have
resulted in a 55% reduction in neonates receiving antibiotics.
However, in a recent meta-analysis of the current published lit-
erature surrounding the SRC (including the study by Goel et al.),
the authors found that many EOS cases were missed by the tool.
This suggests that whilst the intentions of the SRC are a move in
the right direction, research investigating the usefulness of such
tools is still in its infancy.[ 129 ]
Complications of antibiotic use in neonates
Whatever the case, there is growing evidence that prolonged
antibiotic use in this population may be detrimental, especially
in preterm neonates without proven infection, increasing the
risk of mortality, BPD, necrotizing enterocolitis, retinopathy
of prematurity, and periventricular white matter damage.[ 130 ]
Long-term empirical treatment will also affect the neonatal gut
6
[m5GeSdc;September 14, 2023;5:26]
Journal of Intensive Medicine xxx (xxxx) xxx
microbiome, and there is evidence that chronic medical prob-
lems in later life such as childhood asthma may be influenced
by early use of antibiotics.[ 131 ] Currently, however, there are
insufficient data to make clinical recommendations.[ 132 ]
The development and spread of antimicrobial resistance
(AMR) in neonatal populations is also a concern. The WHO
2014 annual report of AMR found that the proportions of E.
coli, Klebsiella pneumonia and Staphylococcus aureus resistant to
commonly used antibacterial agents, exceeded 50% in many
settings.[ 133 ] In newborns cared for in neonatal units, genes
conferring AMR are detectable in bacteria colonizing the in-
testines of preterm infants. In the same units, Staphylococ-
cal species resistant to methicillin and vancomycin are be-
coming more prevalent with a greater mortality associated
with infections from these organisms because they are signif-
icantly more difficult to treat effectively. Furthermore, other
organisms including extended-spectrum 𝛽-lactamase (ESBL)-
producing Gram-negative pathogens that are resistant to
cephalosporins, Gram-negative bacteria resistant to piperacillin-
tazobactam, aminoglycosides, and Klebsiella-resistant to car-
bapenems are slowly emerging.[ 134 ] The Neonatal AntiMicro-
bial Resistance (NeoAMR) launched in 2017 with 39 partici-
pating neonatal units across 12 countries, has thus far reported
preliminary data over 12 months, showing AMR rates amongst
cephalosporins of 26% to 84%, carbapenems of up to 81%, and
glycopeptide of up to 45%.[ 135 ] These data demonstrate the need
for antibiotic stewardship as an increasingly urgent intervention
in neonates.
Is There a Role for Antibiotic Stewardship in Maternal and
Neonatal Clinical Pathways?
To manage sepsis effectively, clinical pathways have been
designed to include recognition, resuscitation, and the timely
administration of appropriate antibiotics.[ 136 ] Guidance is avail-
able for recommended antibiotic regimes for most obstetric in-
dications as well as EOS (Table 1). The overwhelming message
of the surviving sepsis campaigns is that the prompt diagnosis of
sepsis and initiation of broad-spectrum antibiotics is paramount.
Initiatives such as Sepsis Six require that these antibiotics be
commenced within 3 h, and these recommendations have sig-
nificantly reduced mortality rates from sepsis.[ 137 , 138 ] One of the
unintended consequences of the sepsis campaigns has been the
inappropriate use of clinical sepsis pathways in patients who do
not fulfill the criteria for sepsis. Studies have reported that up
to 50% of patients treated with broad-spectrum antibiotics for
sepsis, did not have sepsis.[ 139 ]
The need for maternal antimicrobial stewardship
Clearly, a balance is required between effective treatment
and appropriate antibiotic use. Antibiotic stewardship is re-
quired to optimize antibiotic usage, including rationalizing and
de-escalating or stopping agents, to maintain their effectiveness.
This is important because the incidence of AMR and healthcare-
associated infections (HCAIs) is rising.[ 152 ] In Europe, the AMR
in 2018 as reported by the European AMR Surveillance Net-
work (EARS-Net) indicated more than half of the E. coli and
more than a third of the Klebsiella pneumonia isolates were re-
sistant to at least one antibiotic class.[ 153 ] In LMIC these figures
JID: JOINTM
N.M. Shah, E. Charani, D. Ming et al.
Table 1
Common obstetric indications for antibiotics and recommended regimes.
Indication
GBS prophylaxis
Prophylaxis at caesarean
section
Prophylaxis at caesarean
section
Prophylaxis for operative
vaginal birth
Intrapartum pyrexia
(suspected sepsis)
Mastitis causing sepsis
Caesarean section wound
infection causing sepsis
Endometritis causing
sepsis
Acute pyelonephritis
causing sepsis
Severe sepsis (with no
clear focus)
Toxic shock syndrome
ARTICLE IN PRESS
Causative organisms Antibiotic recommendations
Pregnancy and postnatal for the mother
Antibiotic prophylaxis
GBS Benzylpenicillin
Penicillin allergy (severe):
Vancomycin
Staphylococci Streptococci Single dose first-generation
Gram-negative cephalosporin or penicillin (dose,
30–60 min before surgery)
Staphylococci Streptococci Single dose first-generation
Gram-negative cephalosporin (cefazolin) (dose,
within 60 min before surgery)
Penicillin allergy:
Clindamycin + an
aminoglycoside
Gram-negative anaerobes Single dose of amoxicillin and
Streptococci clavulanic acid
Antibiotic treatment for suspected sepsis
Streptococci Pyrexia with no chorioamnionitis:
Gram-negative organisms Cephalosporin with activity
Anaerobes against GBS (e.g., cefotaxime)
Penicillin allergy: Vancomycin
MRSA Flucloxacillin + clindamycin
Streptococci Penicillin allergy:
Vancomycin + clindamycin or
Clindamycin/teicoplanin
MRSA Flucloxacillin + clindamycin
Streptococci Penicillin allergy:
Vancomycin + clindamycin or
clindamycin/teicoplanin
Gram-negative anaerobes Gentamicin one dose
Streptococci immediately + cefo-
taxime + metronidazole or
gentamicin + clindamycin
Penicillin allergy:
Gentamicin + clin-
damycin + ciprofloxacin
Gram-negative bacteria Gentamicin (once
Staphylococci and only) + cefotaxime or just
Streptococci cefuroxime
Penicillin allergy:
Gentamicin + ciprofloxacin
MRSA, streptococci, Gentamicin (once
Gram-negatives (including only) + meropenem + clin-
ESBL damycin
producers + Pseudomonas) Penicillin allergy:
and anaerobes Clindamycin + gentamicin +
metronidazole + ciprofloxacin
Staphylococci Streptococci Gentamicin (once only) + flu-
cloxacillin + clindamycin or
carbapenem (i.e.,
imipenem/cilastatin or
meropenem); a penicillin with a
beta-lactamase inhibitor (e.g.,
ticarcillin/clavulanate or
piperacillin/tazobactam);
Penicillin allergy:
Gentamicin (once only) + van-
comycin + clindamycin or
gentamicin (once
only) + linezolid or just
vancomycin
7
Journal of Intensive Medicine xxx (xxxx) xxx
Important notes
Alternative: Cephalosporin
Avoid amoxicillin plus
clavulanate in preterm cases due
to risk of necrotizing enterocolitis
Avoid amoxicillin plus
clavulanate in preterm cases due
to risk of necrotizing
enterocolitis.
Azithromycin may be used as an
adjunct for non-elective
caesareans
As soon as possible after birth
and no more than 6 h after birth
Pyrexia with chorioamnionitis:
add metronidazole.
Confirmed MRSA: Vancomycin
ESBLs: gentamicin + meropenem
Confirmed Strep: benzylpenicillin
and clindamycin.
Confirmed methicillin sensitive
Staph:
clindamycin + oxacillin/nafcillin.
Confirmed MRSA: vancomycin
instead of flucloxacillin. Regimen
must contain an antitoxin agent
such as clindamycin or linezolid.
Also Consider IVIG
[m5GeSdc;September 14, 2023;5:26]
References
Prevention of early-onset neonatal
group B streptococcal disease.
Green-top Guideline No. 36. RCOG
2017 [ 140 ]
WHO recommendation on
prophylactic antibiotics for women
undergoing caesarean section.
Geneva: World Health Organization;
2021 [ 141 ]
ACOG Practice Bulletin No. 199: Use
of Prophylactic Antibiotics in labour
and Delivery. Obstet Gynecol. 2018
[ 142 ]
WHO recommendation on routine
antibiotic prophylaxis for women
undergoing operative vaginal birth.
Geneva: World Health Organization;
2021 [ 143 ]
Assisted vaginal birth. Green-top
Guideline No. 26. RCOG, 2020 [ 144 ]
National Maternity Network:
Management of Intrapartum Maternal
Pyrexia in Hospital Guideline. NHS
Scotland. Scottish Perinatal Network.
2022 [ 145 ]
Bacterial Sepsis in Pregnancy.
Green–top Guideline No. 64a. RCOG
2012 [ 146 ]
Mastitis and breast abscess. BMJ Best
Practise. BMJ 2023 [ 147 ]
Bacterial Sepsis in Pregnancy.
Green–top Guideline No. 64a. RCOG
2012 [ 146 ]
Bacterial Sepsis in Pregnancy.
Green–top Guideline No. 64a. RCOG
2012 [ 146 ]
Antibiotic regimens for postpartum
endometritis. Cochrane Database Syst
Rev. 2015 [ 148 ]
Bacterial Sepsis in Pregnancy.
Green–top Guideline No. 64a. RCOG
2012 [ 146 ]
Pyelonephritis (acute): antimicrobial
prescribing. NICE guideline [NG111].
NICE 2018 [ 149 ]
Bacterial Sepsis in Pregnancy.
Green–top Guideline No. 64a. RCOG
2012 [ 146 ]
Bacterial Sepsis in Pregnancy.
Green–top Guideline No. 64a. RCOG
2012 [ 146 ]
Toxic shock syndrome. BMJ Best
Practise. BMJ 2023 [ 150 ]
(continued on next page)
JID: JOINTM
ARTICLE IN PRESS
N.M. Shah, E. Charani, D. Ming et al.
Table 1 (continued)
Indication Causative organisms Antibiotic recommendations
Neonatal (EOS)
Early-onset neonatal Streptococcus (GBS); Gram- Benzylpenicillin with gentamicin
sepsis negative bacteria
ACOG: American College of Obstetricians and Gynecologists; EOS: Early onset neonatal sepsis; ESBLs: Extended-spectrum beta-lactamases; GBS: Group B Strepto-
coccus; IVIG: Intravenous immunoglobulin; MRSA: Methicillin-resistant Staphylococcus aureus; NICE: National Institute for Health and Care Excellence; RCOG: Royal
College of Obstetricians & Gynaecologists; WHO: World Health Organization.
are much higher. For example, in Sudan up to 92% of urinary
E. coli isolates are resistant.[ 154 ] For Sudanese healthcare, the
key drivers of AMR include widespread inappropriate antibiotic
use with up to 65% of hospitalized patients receiving antibi-
otics, and poor access to microbial sensitivity results to guide
better prescribing.[ 155–157 ] In these resource-limited countries,
much of the inappropriate use is due to empirical treatment or
the use of antibiotic prophylaxis.[ 158 ] AMR is estimated to re-
sult in 700,000 deaths each year globally. In 2015 the WHO en-
dorsed a Global Action Plan on Antimicrobial Resistance (GAP)
to address the global problem, and in the UK a government doc-
ument was published in 2019 with the country’s 5-year action
plan, which amongst other goals, was aimed at reducing antibi-
otic use by 15% and specified drug-resistant infections by 10%
over 5 years.[ 159 ] In the maternity setting, patients with peripar-
tum infection have been shown to have resistance to a number
of common organisms encountered in obstetrics such as E. coli,
GBS and GAS, with resistance rates as high as 62% to 81% for
E. coli.[ 160 ] Cohort-specific antibiograms with isolates and their
sensitivities may provide a better way to determine resistance
patterns to guide antibiotic prescribing in maternity.[ 161 ]
Healthcare associated infections
The other consequence of widespread antibiotic use is the
development of HCAIs. The HCAI rate in the UK and devel-
oped countries ranges between 3.5% and 12%. In the inten-
sive care unit (ICU) up to 30% of patients are affected by at
least one episode of HCAI. In comparison, in LMIC the incidence
is greater, averaging between 5.7% and 19.1%, and ICU infec-
tions could be as high as 88%.[ 162 ] Poor reporting and lack of
surveillance schemes mean the true incidence may be higher.
In the UK, annual counts of hospital-acquired Clostridioides dif-
ficile and Methicillin-resistant Staphylococcus aureus (MRSA) in-
fections have been falling since 2007 and are currently show-
ing a 6 and 7-fold decrease respectively when compared to
2007.[ 163 , 164 ] However, these rates have remained unchanged
since 2013 and new efforts are required to ensure a continued
decrease.
The need for neonatal antimicrobial stewardship
Antibiotic prescribing in pediatric populations also remains
a concern and an area that requires attention. The WHO Access,
Watch, and Reserve classification was used in a study across 56
countries to assess the patterns of antibiotic use.[ 165 ] The study
identified significant variation in antibiotic use in hospitalized
neonates and children. One of the key barriers to effective stew-
ardship in neonatal populations remains the lack of metrics for
measuring the quality of antibiotic use.[ 166 ] Much more effort is
8
[m5GeSdc;September 14, 2023;5:26]
Journal of Intensive Medicine xxx (xxxx) xxx
Important notes References
Neonatal infection: antibiotics for
prevention and treatment NICE
guideline [NG195]. NICE 2021 [ 151 ]
needed to establish means of surveillance for effective steward-
ship programs in vulnerable neonatal populations in different
healthcare settings.
Types of antimicrobial stewardship interventions
The WHO has published a framework of antimicrobial stew-
ardship interventions for LMIC, but these are also relevant for
resource-rich countries.[ 167 ] Similarly, NICE has published guid-
ance for the UK.[ 168 ] The interventions are centered around im-
proved education, multidisciplinary working, and better pre-
scribing. In other patient groups, this multifaceted approach has
been shown to reduce antibiotic prescriptions without increas-
ing the risk of complications.[ 169 ] In addition, appropriate an-
tibiotic use can reduce the rates of hospital acquired infections
such as Clostridium difficile.[ 170 ]
In brief, the proposed recommended interventions comprise
[ 167–169 ]
: (1) basic resources to support antibiotic use including
local guidelines for treatment and prophylaxis, access to a mi-
crobiology laboratory and clinical expertise on infections, phar-
macy overview of dosing and duration of treatments. (2) tools
such as the quick sequential (sepsis-related) organ failure as-
sessment (qSOFA) tool for pregnant women, and the Kaiser Per-
manente sepsis risk calculator for neonates can enable better
recognition of sepsis and improve decision-making surrounding
the need for antibiotics. (3) education of healthcare profession-
als to understand indications for treatments, when treatments
should be reviewed, use of decision tools, and the importance of
auditing and recording antibiotic use, prescribing, and clinical
outcomes.(4) use of resources to improve prescribing and effec-
tiveness of antimicrobial stewardship that includes local and re-
gional surveillance of AMR (in common organisms/infections),
rapid testing (such as rapid polymerase chain reaction [PCR] as
discussed later) and restrictive prescribing of certain antibiotics
to prevent resistance.
What Research Gaps Need to be Addressed to Further
Improve Clinical Management and Treatment of Maternal
Sepsis?
Whilst the overall UK prevalence of sepsis-related maternal
deaths remains low, sepsis is still one of the leading causes of di-
rect death in this population. Since 2011, efforts have been made
to highlight the importance of better clinical management of
sepsis in maternal clinical pathways with early recognition and
treatment.[ 146 , 171 ] These have included recommendations from
Mothers and Babies: Reducing Risk through Audits and Confi-
dential Enquiries (MBRRACE), NICE and Royal College of Obste-
tricians & Gynaecologists (RCOG) guidelines as well as screen-
ing and action tools from the UK Sepsis trust.[ 138 , 146 , 171 , 172 ]
JID: JOINTM
ARTICLE IN PRESS
N.M. Shah, E. Charani, D. Ming et al.
Furthermore, initiatives such as the maternity early warning
score (MEWS) and sepsis six have been shown to effectively
predict morbidity in maternity patients and reduce inpatient
mortality respectively.[ 137 , 173 , 174 ] This has been relatively effec-
tive with a reduction in direct deaths due to sepsis in the UK
from 0.63 to 0.44 per 100,000 births from 2009–11 to 2015–17
respectively.[ 175 ] Alongside these, rates of EOS have also been
falling.[ 176 , 177 ] However, many maternal deaths remain poten-
tially preventable.
Tools to improve recognition of maternal sepsis
Better recognition and prophylactic treatment may provide
useful methods to prevent sepsis, particularly during the peri-
partum period. Similar to SRC, obstetric-modified sepsis scoring
tools are useful to objectively risk stratify the severity of sepsis
and direct clinical treatment.[ 178 ] This includes the qSOFA tool
for identifying critically ill obstetric patients.[ 178 , 179 ]
Interventions as prophylaxis
For prophylaxis, the prophylactic antibiotics in the preven-
tion of infection after operative vaginal delivery (ANODE) study
and recent Cochrane review on vaginal antiseptic preparation
prior to Caesarean section found that such interventions resulted
in a 40% reduction in suspected or confirmed infection, and a
64% reduction in post‐Caesarean endometritis respectively with
likely limited impact on AMR.[ 20 , 180 ] In LMIC, implementing
these as part of a series of interventions to reduce maternal and
neonatal sepsis would be required in order to be effective.[ 181 ]
Immunomodulators
In addition to antibiotics, research to find new methods to
enhance either the acute response to infection or the recovery
phase during sepsis are potentially important areas for future
work. Poor acute immune responses have been associated with
an increased risk of developing secondary infections, whilst ex-
cessive inflammatory responses are associated with an increased
risk of developing downstream complications from sepsis such
as cardiovascular collapse.[ 182 , 183 ]
Steroid immune suppression
Respiratory complications during sepsis are likely to ben-
efit most from immunosuppression. Animal study data sug-
gests that this may be particularly relevant in pregnancy. A
more recent example of a clinical trial of immunomodulators
to modify the host response is the novel Randomised Evalua-
tion of COVID-19 Therapy (RECOVERY Trial) comparing dif-
ferent treatments aimed at altering the host response to SARS-
CoV-2 virus (NCT04381936). In patients recruited during the
first wave of the pandemic between March and June 2020, dex-
amethasone treatment significantly lowered 28-day mortality in
patients receiving either invasive mechanical ventilation or oxy-
gen alone.[ 184 ] Importantly and unlike many other clinical tri-
als, RECOVERY explicitly included pregnant women during re-
cruitment. However, despite showing a clear clinical benefit, far
fewer critically ill pregnant women compared to non-pregnant
women received steroids (9.3% vs. 22.6%).
9
[m5GeSdc;September 14, 2023;5:26]
Journal of Intensive Medicine xxx (xxxx) xxx
Immunotherapy agents
The RECOVERY trial collaborative’s subsequent work in-
vestigating the benefits of Tocilizumab treatment, which is a
monoclonal antibody targeted against the interleukin-6 recep-
tor, found that in hospitalized COVID-19 patients with hypoxia
and systemic inflammation, Tocilizumab not only improved sur-
vival, but it also reduced the likelihood of the composite end-
point of invasive mechanical ventilation or death.[ 185 ]
To date, randomized controlled trials conducted using
immune-modulators such as Granulocyte-macrophage colony-
stimulating factor (GM-CSF) and IgM-enriched immunoglob-
ulin have shown promising results with improved resolution
from infection and reduced mortality risk respectively.[ 186 , 187 ]
Other potential targets for improved host responses include
IFN-𝛾, IL-7, and IL-15, which have been investigated ex vivo,
with evidence showing that their use results in improved leu-
cocyte responses.[ 188–191 ] Other agents are an IL-1R antagonist
(Anakinra), shown to be safe during pregnancy in small studies
and used in sepsis in non-pregnant patients (macrophage ac-
tivating syndrome) to reduce mortality.[ 192 , 193 ] Unfortunately,
comparing previous clinical studies to make clear recommen-
dations is difficult due to their heterogeneous study designs
with myriad differences including treatment dosing, inclusion
and exclusion criteria, supportive treatments, settings, and en-
listed study populations. Furthermore, circulating cytokine lev-
els vary during severe sepsis meaning that clinical benefit may
only be seen in some patients and suggesting that their use
should be reserved for certain situations.[ 194 ] Indeed, anti-TNF-𝛼
immunotherapy is associated with an overall reduction in mor-
tality and improved survival in patients with high serum lev-
els of IL-6.[ 195 ] Observational data from patients taking disease
modifying drugs for immune-mediated medical conditions such
as rheumatoid arthritis suggest immune suppression may help
to prevent unregulated host responses to sepsis.[ 196 ]
Clearly in current times with emerging viral pandemics, a
significant global incidence of bacterial sepsis, high AMR, and
the need for better antibiotic stewardship, novel methods of reg-
ulating host responses to infection are an important area of re-
search. A good example is the GBS vaccine, which has thus far
been investigated in early clinical trials in pregnancy and shows
a great deal of promise.[ 197 ] Furthermore, the development of
such a vaccine has been identified as a research priority by the
WHO.
What is the Evidence for Personalised Approaches to Treat
Maternal Infections?
Preterm birth and chorioamnionitis provide an area of clini-
cal research where a personalized approach to the management
of infection may reduce the risk of maternal sepsis as well as im-
prove neonatal outcomes. In fact, infection-driven preterm birth
is one of the only aetiologies that has a proven direct causal link.
Preterm birth as a model for obstetric infections
It is increasingly perceived that the uterine cavity and amni-
otic fluid are not sterile, but that they both contain a rich micro-
biome that is different in each compartment.[ 198 ] The uterine mi-
crobiome appears synchronous with vaginal bacterial colonies
and is affected by age, endometrial inflammation (endometri-
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N.M. Shah, E. Charani, D. Ming et al. Journal of Intensive Medicine xxx (xxxx) xxx

tis), and mode of birth (cesarean section or vaginal birth)[ 199 ]
whereas the amniotic cavity appears to share its constituent mi-
crobiota with the fetus, exposing it to microbes throughout its
in-utero development probably by ingestion.[ 200 , 201 ] In almost
60% of cases of PTL is thought to be due to microbial invasion
of the amniotic cavity (MIAC). These invading organisms will of-
ten include those linked with preterm birth such as Mycoplasma
and Ureaplasma species,[ 202 , 203 ] which are typically not present
in mid-trimester pregnancies.[ 204 ]
More recently, in a non-human primate model of preterm
birth using an intrauterine injection of E. coli, administration
of systemic antibiotics 24 h after injecting E. coli was signifi-
cantly effective at eradicating maternal bacteremia. However,
treatment did not resolve choriodecidual or amnion tissue in-
flammation nor preterm birth.[ 211 ] These studies suggest that
antibiotic prophylaxis, and appropriate treatment of chorioam-
nionitis can prevent maternal sepsis but they may not improve
fetal or neonatal outcomes. So, how can clinical teams rapidly
detect bacterial infections and target antibiotic treatments?

Antibiotics to treat intra-amniotic infection New methods to detect pathogens

Professor Sara Kenyon and the ORACLE collaborative group
in the early 2000′s designed a randomized controlled trial of
erythromycin or co-amoxiclav given to pregnant women pre-
senting with PTL and/or preterm ruptured membranes. Impor-
tantly, they showed treatment resulted in a significant reduction
in maternal infection.[ 205 ] Their findings also demonstrated a
short-term improvement in neonatal morbidity, but no reduc-
tion in perinatal mortality or improvement in the health of the
children at age seven.[ 206–208 ] However, when administered to
the intact membrane group in PTL, treatment with either an-
tibiotic did not improve neonatal outcomes.[ 209 , 210 ]
Whereas traditional microscopy and culture-based methods
have often described sterile or culture-negative inflammation in
amniotic fluid with preterm birth, new techniques using nucleic
acid amplification testing (NAAT) or amplification of prokary-
otic 16S subunit ribosomal DNA have proven to be better de-
tection tools, identifying a broad range of organisms as well as
those that prove to be more difficult to detect using standard
culture-based methods such as Ureaplasma.[ 212 ]
One of the drawbacks of 16S is the speed of the assay since
a reference laboratory is usually required meaning that results
can take several days from sample collection. Furthermore, dif-

Figure 2. Use of technologies to detect systemic and intra-amniotic infection. Ascending organisms MIAC into the amniotic cavity will be phagocytosed by neu-
trophils, PAMPs originating from these organisms will activate macrophages causing these cells to release pro-inflammatory cytokines (such as IL-6). IL-6 is also
produced by activated monocytes, and amnion cells along with other reproductive/pregnancy tissue as part of an inflammatory immune response. Amniotic fluid
can be sampled (by amniocentesis) and used to detect both intra-amniotic infection and inflammation. Systemic infection can be detected from peripheral blood.
Traditional NAAT methods can be relatively rapid and are highly sensitive but lack the isolation of AMR. 16S rRNA methods are an alternative, metagenomics
gives better coverage, and new methods such as multiplex PCR are rapid and suitable as a POC. Inflammation can be measured by ELISA, rapid chemiluminescent
immunoassay and by a lateral flow POC.
AMR: Antimicrobial resistance; ELISA: Enzyme linked immunosorbent assay; IL-6: Interleukin-6; MIAC: Microbial invasion of the amniotic cavity; NAAT: Nucleic
acid amplification test; PAMPs: Pathogen associated molecular patterns; PCR: Polymerase chain reaction; POC: Point-of-care test; rRNA: ribosomal RNA.

10
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N.M. Shah, E. Charani, D. Ming et al. Journal of Intensive Medicine xxx (xxxx) xxx

ferentiating between commensals and colonizing organisms can
be difficult. By comparison, culture and sensitivities may take
48 h or more but provide more clinically useful information.
New techniques that can identify organisms quickly, and those
that also sequence any AMR genes have begun to emerge, which
provide a more comprehensive output for clinical application.
For example, in the context of labor and birth, NAAT of GBS pro-
vides rapid diagnosis with good sensitivity and specificity (91%
and 98% respectively) to enable more accurate management of
laboring mothers.[ 213 ] Methods such as nanopore metagenomic
sequencing can genotype without the need for amplification or
labeling. Proof of concept studies have demonstrated the fea-
sibility of nanopore technology in respiratory and blood sam-
ples with good concordance with traditional culture and sensi-
tivity, thus providing clinical teams the ability to identify or-
ganisms, and resistance patterns and rapidly direct appropriate
anti-microbial treatments.[ 214 , 215 ]
Improving the precision of identifying clinically relevant
infections
elevated levels of IL-6 and labeled these as infective pathogens.
Concentrations of IL-6 in the fluid were combined with the intra-
amniotic micro-organisms identified, to create a multivariate
regression model for predictors of latency to birth, composite
perinatal morbidity, and mortality rates, adjusted for gestational
age. Their results showed that IL-6 was a better predictor of poor
outcomes than the microbial species alone, which was in keep-
ing with previous reports.[ 216 , 217 ]
Equally, the Premature Rupture Membranes and threatened
PTL - a Personalised Approach (PROMPT) will investigate the
clinical benefits of rDNA methods using a multiplex-based PCR
system to detect bacteria and cytokine profiling of amniotic
fluid with the aim of improving latency to birth as well as ma-
ternal infection rates in women with ruptured membranes and
PTL (Figure 2).[ 218 ] Indeed, the use of omics, whereby molecule
groups can be assessed from the same biological sample, may
provide a comprehensive look at the pathophysiology of the pro-
cess in question such as with sepsis.[ 219 ]
Conclusions

However, with early detection at presentation and prior to
pregnant women developing overt clinical signs of severe in-
fection, can this technology be further refined to establish a
likelihood of severity? Here, cytokine profiling of reservoirs of
organisms such as the amniotic cavity may be helpful. Combs
et al.[ 202 ] investigated amniotic fluid infection in women with
spontaneous PTL with intact fetal membranes using amniocen-
tesis alongside standard culture and 16S rDNA methods. They
correlated the most prevalent organisms in amniotic fluid with
The key strategies discussed in this manuscript are sum-
marised in Figure 3. Maternal sepsis remains a global threat
to safe pregnancy, childbirth, and maternal and neonatal out-
comes. In the UK, sepsis rates have steadily been falling and
emerging research such as the ANODE study and Cochrane re-
view on pre-Caesarean section vaginal preparation will reduce
these rates further. Despite this, sepsis remains an important
cause of maternal morbidity and mortality in the UK. Initiatives
such as the global maternal sepsis study (GLOSS) and NeoAMR,

Figure 3. Key strategies for the management of sepsis in pregnancy. This flowchart summaries the maternal neonatal complications, the importance of prompt
antibiotic use but the potential issues with the current usage, how antibiotic stewardship can be achieved and the potential for adjunctive treatments.
AMR: Antimicrobial resistance; ANODE: Prophylactic antibiotics in the prevention of infection after operative vaginal delivery; GLOSS: Global maternal sepsis study;
MBRRACE: Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries; NAAT: Nucleic acid amplification test; PCR: Polymerase chain reaction;
qSOFA: quick Sequential organ failure assessment; rDNA: ribosomal DNA; SRC: Sepsis risk calculator.

11
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N.M. Shah, E. Charani, D. Ming et al.
will help to provide a framework for reporting maternal infec-
tions as well as reflecting the burden of neonatal unit-level AMR
worldwide. This will guide the development of core practices for
managing maternal and neonatal infections. Early and appropri-
ate detection of both maternal and neonatal infections is key and
tools such as qSOFA and SRC have the potential to influence an-
tibiotic stewardship and thus clinical care in the acute setting.
However, further research is required on their use. Adjunctive
immunotherapy is another potential avenue for research in sep-
sis whereby the host response can be altered to fit the patient’s
needs in terms of both clinical deterioration and immune re-
sponse. This introduces the concept of personalized medicine
where combinations of antibiotics and immunotherapy agents
are used together to improve the clinical outcome. Individual-
ized risk stratification rather than the use of population-based
scores and protocols will help to achieve this. There is still some
way to go before this is a clinically viable option but research to
date has yielded promising results. It remains critical in the cur-
rent climate where patients often face multi-organism infection
and widespread antibiotic drug resistance, to investigate novel
methods to diagnose and manage sepsis.
Author Contributions
NMS was responsible for the conception of the article topic,
undertook the primary literature search, reviewed, and sum-
marised current evidence, was responsible for writing the ini-
tial and revised drafts based on comments and suggestions from
co‐authors and submitted the final version. EC, DM, and FCC
all reviewed each draft with critical revision of intellectual con-
tent, reviewed the current literature and incorporated this into
the article. MRJ was involved in the conception of the article
topic, critically revised the intellectual content, and advised on
the structure of the article, content, and current areas of debate.
All authors read and approved the final version.
Acknowledgements
Images used in the figures were created with Biorender.com.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Ethics Statement
Not applicable.
Conflict of Interest
The authors declare that they have no known competing fi-
nancial interests or personal relationships that could have ap-
peared to influence the work reported in this paper.
Data Availability
The data sets generated during and/or analyzed during the
current study are available from the corresponding author upon
reasonable request.
12
[m5GeSdc;September 14, 2023;5:26]
Journal of Intensive Medicine xxx (xxxx) xxx
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